International Consortium to Identify Genes and Interactions Controlling Oral Clef

描述(申请人提供)：口腔裂，包括唇裂(CL)、唇腭裂(CLP)和腭裂(CP)，统称为人类最常见的出生缺陷之一。口腔裂具有复杂和异质性的病因，遗传和环境因素都有强有力的证据。候选基因研究和全基因组连锁研究已经产生了令人信服但不一致的证据，证明多个基因控制着口裂的风险，几项研究表明基因与环境暴露之间存在相互作用的证据，特别是母亲吸烟和营养物质。我们已经组建了一个由经验丰富的研究人员组成的财团，他们积累了大量关于病例及其家人(主要是病例父母三人组)的DNA样本，这些样本现在可用于全基因组研究，这代表着口腔裂遗传学研究的下一个水平。1.利用高通量单核苷酸多态(SNP)基因分型技术，对1例孤立性、非综合征性口腔裂(CL、CLP或CP)及其双亲确定的2000例亲本三联体进行全基因组分析，以检测连锁和LD。初步分析将包括对基因效应的单独测试，适当的单倍型分析和允许群体间异质性的较大染色体区域的新作图方法。2.测试基因与常见的母亲暴露之间的相互作用，包括维生素补充剂、吸烟和饮酒(通过访谈收集)，这些因素已被认为是口腔裂的环境危险因素。来自一个组成人群(犹他州)的营养状况的血清生物标记物措施的可用性允许对GxE相互作用进行重要的进一步测试。3.测试基因之间的相互作用，以解释文献中关于控制口腔裂风险的基因的一些相互矛盾的结果。这项提议提供了一个独特的机会来扩大和扩大对控制口腔裂隙风险的基因的搜索，创造了在人群中快速复制的机会，并将指导对控制正常颅面发育的基因的进一步分子研究。

DESCRIPTION (provided by applicant): Oral clefts, which include cleft lip (CL), cleft lip and palate (CLP) and cleft palate (CP), and collectively represent one of the most common birth defects in humans. Oral clefts have a complex and heterogeneous etiology, with strong evidence for both genetic and environmental causal factors. Candidate gene studies and genome wide linkage studies have yielded compelling but inconsistent evidence that multiple genes control risk to oral clefts, and several studies have shown evidence for interaction between genes and environmental exposures, especially maternal smoking and nutrients. We have assembled a consortium of experienced investigators who have accumulated a very large collection of DNA samples on cases and their families (mostly case-parent trios) that are now available for genome wide studies, which represents the next level of genetic investigation for oral clefts. Specific aims are: 1. To conduct a genome wide analysis on 2000 case-parent trios ascertained through a case with isolated, non-syndromic oral cleft (CL, CLP or CP) and their parents using high throughput genotyping of single nucleotide polymorphic (SNP) markers to test for linkage and LD. The initial analysis will consist of individual tests for gene effects, with appropriately haplotype analysis and novel mapping approaches for larger chromosomal regions that allows for heterogeneity among populations. 2. To test for interaction between genes and common maternal exposures including vitamin supplementation, cigarette smoking and alcohol consumption (collected by interview) which have been implicated as environmental risk factors for oral clefts. Availability of serum biomarker measures of nutritional status from one component populations (Utah) allows important further tests for GxE interactions. 3. To test for interaction between genes that may explain some of the conflicting results in the literature with regard to genes controlling risk to oral clefts. This proposal offers a unique opportunity to expand and extend the search for genes controlling risk to oral clefts, creates the opportunity for quick replication across populations and will direct further molecular studies of genes controlling normal craniofacial development.